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The thermodynamics of polyamide-DNA recognition: hairpin polyamide binding in the minor groove of duplex DNA

Pilch, Daniel S. and Poklar, Nataša and Baird, Eldon E. and Dervan, Peter B. and Breslauer, Kenneth J. (1999) The thermodynamics of polyamide-DNA recognition: hairpin polyamide binding in the minor groove of duplex DNA. Biochemistry, 38 (7). pp. 2143-2151. ISSN 0006-2960. doi:10.1021/bi982628g.

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Crescent-shaped synthetic ligands containing aromatic amino acids have been designed for specific recognition of predetermined DNA sequences in the minor groove of DNA. Simple rules have been developed that relate the side-by-side pairings of Imidazole (Im) and Pyrrole (P) amino acids to their predicted target DNA sequences. We report here thermodynamic characterization of the DNA-binding properties of the six-ring hairpin polyamide, ImImPy-γ-PyPyPy-β-Dp (where γ= γ-aminobutyric acid, β= β-alanine, and Dp = dimethylaminopropylamide). Our data reveal that, at 20 degrees C, this ligand binds with a relatively modest 1.8-fold preference for the designated match site, 5'-TGGTA-3', over the single base pair mismatch site, 5'-TGTTA-3'. By contrast, we find that the ligand exhibits a 102-fold greater affinity for its designated match site relative to the double base pair mismatch site, 5'-TATTA-3'. These results demonstrate that the energetic cost of binding to a double mismatch site is not necessarily equal to twice the energetic cost of binding to a single mismatch site. Our calorimetrically measured binding enthalpies and calculated entropy data at 20 degrees C reveal the ligand sequence specificity to be enthalpic in origin. We have compared the DNA-binding properties of ImImPy-γ-PyPyPy-β-Dp with the hairpin polyamide, ImPyPy-γ-PyPyPy-β-Dp (an Im --> Py "mutant"). Our data reveal that both ligands exhibit high affinities for their designated match sites, consistent with the Dervan pairing rules. Our data also reveal that, relative to their corresponding single mismatch sites, ImImPy-γ-PyPyPy-β-Dp is less selective than ImPyPy-γ-PyPyPy-β-Dp for its designated match site. This result suggests, at least in this case, that enhanced binding affinity can be accompanied by some loss in sequence specificity. Such systematic comparative studies allow us to begin to establish the thermodynamic database required for the rational design of synthetic polyamides with predictable DNA-binding affinities and specificities.

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Dervan, Peter B.0000-0001-8852-7306
Additional Information:© 1999 American Chemical Society. Received November 4, 1998. This work was supported by National Institutes of Health Grants GM-23509 (K.J.B.), GM-34469 (K.J.B.), CA-47995 (K.J.B.), CA-77433 (D.S.P.), and GM-27681 (P.B.D.) and a Howard Hughes Medical Institute predoctoral fellowship to E.E.B.
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Howard Hughes Medical Institute (HHMI)UNSPECIFIED
Issue or Number:7
Record Number:CaltechAUTHORS:20160510-093229012
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Official Citation:The Thermodynamics of Polyamide−DNA Recognition:  Hairpin Polyamide Binding in the Minor Groove of Duplex DNA Daniel S. Pilch,, Nataša Poklar, Eldon E. Baird, Peter B. Dervan, and Kenneth J. Breslauer Biochemistry 1999 38 (7), 2143-2151 DOI: 10.1021/bi982628g
Usage Policy:No commercial reproduction, distribution, display or performance rights in this work are provided.
ID Code:66861
Deposited By: Victoria Brennan
Deposited On:17 May 2016 22:50
Last Modified:11 Nov 2021 00:23

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